{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:48:17Z","timestamp":1792608497428,"version":"4.5.0"},"posted":{"date-parts":[[2025,4,7]]},"group-title":"Neuroscience","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R21 NS125201"],"award-info":[{"award-number":["R21 NS125201"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008474","name":"New Jersey Commission on Brain Injury Research","doi-asserted-by":"crossref","award":["CBIR25IRG016"],"award-info":[{"award-number":["CBIR25IRG016"]}],"id":[{"id":"10.13039\/100008474","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Leukemia Inhibitory Factor (LIF) is an injury-induced cytokine that peaks 48 hours after a traumatic brain injury (TBI). Juvenile LIF haplodeficient mice exhibit desynchronized glial responses, increased neurodegeneration, decreased axonal conductivity and behavioral deficits after a concussive head injury. Given the necessity of LIF during the acute recovery phase after injury, we hypothesized that intranasal LIF (IN-LIF) treatment would prevent neurodegeneration when administered during the chronic recovery period from a mild TBI (mTBI). Young adult male CD1 mice were subjected to a midline, closed-head frontal cortex injury using a flat metal impactor with a 3mm tip to induce a mTBI. In the 6-8 weeks post-mTBI, known to precede axonal atrophy in this mTBI model, two doses of 40 ng and 100 ng of LIF were administered twice daily, 5 days\/week for two consecutive weeks. Sensorimotor functions were assessed at 4 and 8 weeks post mTBI, followed by ex-vivo brain magnetic resonance imaging at 9.4T and histopathology. mTBI mice showed sensorimotor deficits at 4 weeks, which worsened by 8 weeks post-injury. IN-LIF treatment prevented the progressive sensorimotor loss seen in the vehicle-treated controls. Increased mean diffusivity and decreased fractional anisotropy were observed in the corpus callosum and prefrontal cortex of mTBI brains. In a dose-dependent manner, IN-LIF prevented the mTBI-induced mean diffusivity increase and fractional anisotropy decrease. Histologically, there was significantly less astrogliosis, microgliosis and axonal injury in the IN-LIF treated mice vs. controls. These results support the therapeutic potential of IN-LIF to reduce delayed neurodegeneration and improve neurological outcomes after mTBIs.<\/jats:p>","DOI":"10.1101\/2025.04.07.647435","type":"posted-content","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T23:15:18Z","timestamp":1744067718000},"source":"Crossref","is-referenced-by-count":1,"title":["Intranasal Leukemia Inhibitory Factor as a late-stage treatment for delayed white matter damage in concussive head injury"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2145-9115","authenticated-orcid":false,"given":"Veera","family":"D\u2019Mello","sequence":"first","affiliation":[{"name":"Rutgers-New Jersey Medical School, Newark, NJ, 07103 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2973-7228","authenticated-orcid":false,"given":"Jelena","family":"Mihailovic","sequence":"additional","affiliation":[{"name":"Yale University, Magnetic Resonance Research Center, New Haven, CT, 06520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidra","family":"Ali","sequence":"additional","affiliation":[{"name":"Rutgers-New Jersey Medical School, Newark, NJ, 07103 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0851-6621","authenticated-orcid":false,"given":"Basavaraju G.","family":"Sanganahalli","sequence":"additional","affiliation":[{"name":"Yale University, Magnetic Resonance Research Center, New Haven, CT, 06520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Coman","sequence":"additional","affiliation":[{"name":"Yale University, Magnetic Resonance Research Center, New Haven, CT, 06520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7822-4002","authenticated-orcid":false,"given":"Fahmeed","family":"Hyder","sequence":"additional","affiliation":[{"name":"Yale University, Magnetic Resonance Research Center, New Haven, CT, 06520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merisha","family":"Fernando","sequence":"additional","affiliation":[{"name":"Rutgers-New Jersey Medical School, Newark, NJ, 07103 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Mampilly","sequence":"additional","affiliation":[{"name":"Rutgers-New Jersey Medical School, Newark, NJ, 07103 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridhar S.","family":"Kannurpatti","sequence":"additional","affiliation":[{"name":"Rutgers-New Jersey Medical School, Newark, NJ, 07103 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1264-7309","authenticated-orcid":false,"given":"Steven W.","family":"Levison","sequence":"additional","affiliation":[{"name":"Rutgers-New Jersey Medical School, Newark, NJ, 07103 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041209472038000_2025.04.07.647435v3.1","doi-asserted-by":"publisher","DOI":"10.1097\/YCO.0b013e328344698b"},{"key":"2026041209472038000_2025.04.07.647435v3.2","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-015-0591-8"},{"key":"2026041209472038000_2025.04.07.647435v3.3","doi-asserted-by":"crossref","unstructured":"McKee AC , Mez J , Abdolmohammadi B , Butler M , Huber BR , Uretsky M , et al. Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts. JAMA Neurology. 2023.","DOI":"10.1001\/jamaneurol.2023.2907"},{"key":"2026041209472038000_2025.04.07.647435v3.4","doi-asserted-by":"publisher","DOI":"10.55782\/ane-2011-1821"},{"key":"2026041209472038000_2025.04.07.647435v3.5","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2011.2055"},{"key":"2026041209472038000_2025.04.07.647435v3.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2012.01.051"},{"key":"2026041209472038000_2025.04.07.647435v3.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2007.05.007"},{"issue":"1","key":"2026041209472038000_2025.04.07.647435v3.8","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s40478-021-01193-8","article-title":"Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures","volume":"9","year":"2021","journal-title":"Acta neuropathologica communications"},{"issue":"5","key":"2026041209472038000_2025.04.07.647435v3.9","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.3892\/mmr.2017.6350","article-title":"Protection of FK506 against neuronal apoptosis and axonal injury following experimental diffuse axonal injury","volume":"15","year":"2017","journal-title":"Mol Med Rep"},{"key":"2026041209472038000_2025.04.07.647435v3.10","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx339"},{"key":"2026041209472038000_2025.04.07.647435v3.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2024.07.003"},{"key":"2026041209472038000_2025.04.07.647435v3.12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0819-18.2018"},{"key":"2026041209472038000_2025.04.07.647435v3.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2019.113040"},{"key":"2026041209472038000_2025.04.07.647435v3.14","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-015-9719-7"},{"key":"2026041209472038000_2025.04.07.647435v3.15","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.20588"},{"key":"2026041209472038000_2025.04.07.647435v3.16","doi-asserted-by":"publisher","DOI":"10.1038\/nature12880"},{"key":"2026041209472038000_2025.04.07.647435v3.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2016.05.016"},{"key":"2026041209472038000_2025.04.07.647435v3.18","doi-asserted-by":"publisher","DOI":"10.1093\/scan\/nst063"},{"key":"2026041209472038000_2025.04.07.647435v3.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2009.06.019"},{"key":"2026041209472038000_2025.04.07.647435v3.20","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2011.233"},{"key":"2026041209472038000_2025.04.07.647435v3.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2015.07.001"},{"key":"2026041209472038000_2025.04.07.647435v3.22","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1997.6536"},{"key":"2026041209472038000_2025.04.07.647435v3.23","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-198"},{"issue":"1","key":"2026041209472038000_2025.04.07.647435v3.24","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1468-1331.2007.01995.x","article-title":"Leukaemia inhibitory factor is over-expressed by ischaemic brain tissue concomitant with reduced plasma expression following acute stroke","volume":"15","year":"2008","journal-title":"Eur J Neurol"},{"key":"2026041209472038000_2025.04.07.647435v3.25","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2015.4234"},{"key":"2026041209472038000_2025.04.07.647435v3.26","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23929"},{"key":"2026041209472038000_2025.04.07.647435v3.27","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(98)00360-7"},{"key":"2026041209472038000_2025.04.07.647435v3.28","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20321"},{"key":"2026041209472038000_2025.04.07.647435v3.29","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.2009.01179.x"},{"key":"2026041209472038000_2025.04.07.647435v3.30","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3047-06.2006"},{"key":"2026041209472038000_2025.04.07.647435v3.31","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000165"},{"key":"2026041209472038000_2025.04.07.647435v3.32","doi-asserted-by":"publisher","DOI":"10.1089\/neur.2021.0075"},{"key":"2026041209472038000_2025.04.07.647435v3.33","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.20962"},{"key":"2026041209472038000_2025.04.07.647435v3.34","unstructured":"Franklin KBJ , Paxinos G . Paxinos and Franklin\u2019s the Mouse Brain in Stereotaxic Coordinates, Compact: The Coronal Plates and Diagrams: Elsevier Science; 2019."},{"key":"2026041209472038000_2025.04.07.647435v3.35","first-page":"209","article-title":"BioImage Suite: An integrated medical image analysis suite: An update","volume":"2006","year":"2006","journal-title":"Insight J"},{"key":"2026041209472038000_2025.04.07.647435v3.36","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.783"},{"key":"2026041209472038000_2025.04.07.647435v3.37","doi-asserted-by":"publisher","DOI":"10.1006\/jmrb.1996.0086"},{"key":"2026041209472038000_2025.04.07.647435v3.38","doi-asserted-by":"publisher","DOI":"10.1006\/cbmr.1996.0014"},{"key":"2026041209472038000_2025.04.07.647435v3.39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0159442"},{"key":"2026041209472038000_2025.04.07.647435v3.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.10.030"},{"key":"2026041209472038000_2025.04.07.647435v3.41","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.315051"},{"key":"2026041209472038000_2025.04.07.647435v3.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2013.01.028"},{"key":"2026041209472038000_2025.04.07.647435v3.43","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlw045"},{"key":"2026041209472038000_2025.04.07.647435v3.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113207"},{"issue":"4","key":"2026041209472038000_2025.04.07.647435v3.45","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.3390\/ijms24043390","article-title":"Biomaterials-Enhanced Intranasal Delivery of Drugs as a Direct Route for Brain Targeting","volume":"24","year":"2023","journal-title":"International journal of molecular sciences"},{"key":"2026041209472038000_2025.04.07.647435v3.46","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2015.01805"},{"key":"2026041209472038000_2025.04.07.647435v3.47","doi-asserted-by":"publisher","DOI":"10.1080\/02699052.2018.1531301"},{"key":"2026041209472038000_2025.04.07.647435v3.48","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2017.5124"},{"key":"2026041209472038000_2025.04.07.647435v3.49","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-21-07922.2003"},{"key":"2026041209472038000_2025.04.07.647435v3.50","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23469"},{"key":"2026041209472038000_2025.04.07.647435v3.51","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1326-y"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.04.07.647435","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T16:47:30Z","timestamp":1776012450000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.04.07.647435"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,7]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2025.04.07.647435","relation":{},"subject":[],"published":{"date-parts":[[2025,4,7]]},"subtype":"preprint"}}